Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging
Open accessAbstract
Oxidative DNA damage accumulates with age and is repaired primarily via the base excision repair (BER) pathway. This process is initiated by DNA glycosylases, which remove damaged bases in a substrate-specific manner. The DNA glycosylases human 8-oxoguanine-DNA glycosylase (OGG1) and NEIL1, a mammalian homolog ofEscherichia coli endonuclease VIII, have overlapping yet distinct substrate specificity. Recently, we reported that OGG1 binds to the Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein that poly(ADP-ribosyl)ates nuclear proteins in response to DNA damage and other cellular signals. Here, we show that NEIL1 and PARP-1 bind both in vitro and in vivo. PARP-1 binds to the C-terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP-1. NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP-1. Furthermore, NEIL-deficient fibroblasts have impaired poly(ADP-ribosyl)ation of cellular proteins after DNA damage, which can be rescued by NEIL1 expression. Additionally, PARP-1 inhibits NEIL1 incision activity in a concentration-dependent manner. Consistent with the idea of impaired DNA repair during aging, we observed differential binding of PARP-1 to recombinant NEIL1 in older mice compared to younger mice. These data further support the idea that dynamic interplay between different base excision repair proteins is important for efficient BER.
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PARP1 activity positively correlates with longevity across species.
“It has been observed that PARP1 activity positively correlates with longevity in different species (Bakondi et al., 2011; Beneke et al., 2010; Noren-Hooten et al., 2012)”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Noren-Hooten et al., 2012
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McCullough, A. K., Minko, I. G., Luzadder, M. M., Zuckerman, J. T., Vartanian, V. L., Jaruga, P., Dizdaroğlu, M., & Lloyd, R. S. (2025) · DNA repair · doi:10.1016/j.dnarep.2025.103820 · Cited by 8 · see citing works
Protein–Protein Interactions in Base Excision Repair
Rathnaiah, G., & Sweasy, J. B. (2025) · Biomolecules · doi:10.3390/biom15060890 · Cited by 8 · see citing works
Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status
Ramaker, M. E., Greenspan, S. L., Resnick, N. M., Perera, S., Gurkar, A. U., Absher, D., & Levine, A. S. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01277 · Cited by 7 · see citing works
“Comparative studies among 13 mammalian species found that the enzymatic activity of PARP1 positively correlates with maximum lifespan in various mammals, including humans (Bürkle et al., 1992; Muiras et al., 1998; Piskunova et al., 2008; Noren Hooten et al., 2012).”
BackgroundDyrkheeva, N. S., Malakhova, A. A., Zakharenko, A. L., Okorokova, L. S., Shtokalo, D. N., Pavlova, S. V., Medvedev, S. P., Zakian, S. M., Nushtaeva, A. A., Tupikin, A. E., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065148 · Cited by 7 · see citing works
Romano, R., Zaravinos, A., Liadaki, K., Caridha, R., Lundin, J., Carlsson, G., Winiarski, J. H., Pan‐Hammarström, Q., & Hammarström, L. L. G. (2017) · Clinical Immunology · doi:10.1016/j.clim.2017.01.006 · Cited by 6 · see citing works
Noncatalytic Domains in DNA Glycosylases
Torgasheva, N. A., Diatlova, E. A., Грин, И. Р., Endutkin, A. V., Mechetin, G. V., Vokhtantsev, I. P., Yudkina, A. V., & Zharkov, D. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137286 · Cited by 4 · see citing works
Hypersensitivity of mouse NEIL1-knockdown cells to hydrogen peroxide during S phase
Yamamoto, R., Ohshiro, Y., Shimotani, T., Yamamoto, M., Matsuyama, S., Ide, H., & Kubo, K. (2014) · Journal of Radiation Research · doi:10.1093/jrr/rru021 · Cited by 3 · see citing works
“Interaction of hNEIL1 with poly (ADP-ribose) polymerase-1 (PARP-1) [27], a DNA damage sensor, has been observed Fig.”
BackgroundPARP1 Gene Knockout Suppresses Expression of DNA Base Excision Repair Genes
Zakharenko, A. L., Malakhova, A. A., Dyrkheeva, N. S., Okorokova, L. S., Medvedev, S. P., Zakian, S. M., Kabilov, M. R., Tupikin, А. Е., & Lavrik, O. I. (2023) · Doklady Biochemistry and Biophysics · doi:10.1134/s1607672922700028 · Cited by 2 · see citing works
“The association between PARP1 and NEIL1 is highlighted in red [20].”
BackgroundResultInfluentialMultitasking Roles for Poly(ADP-ribosyl)ation in Aging and Longevity
Mangerich, A., & Bürkle, A. (2015) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-14151-0_6 · Cited by 2 · see citing works
The DNA Glycosylases that Recognize and Remove Free Radical-damaged Pyrimidines
Lee, A. J., & Wallace, S. S. (2016) · WORLD SCIENTIFIC eBooks · doi:10.1142/9789814719735_0004 · Cited by 2 · see citing works
Neurauter, C. G., Pannone, M., de Sousa, M. M. L., Wang, W., Kuśnierczyk, A., Luna, L., Sætrom, P., Scheffler, K., & Bjørås, M. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.01.037 · Cited by 1 · see citing works
Investigating the biological role of human NEIL3
Rödl, T. (2013) · University of Salford Institutional Repository (University of Salford)
PARP1 GENE KNOCKOUT SUPPRESSES EXPRESSION OF DNA BASE EXCISION REPAIR GENES
Zakharenko, A. L., Malakhova, A. A., Dyrkheeva, N. S., Okorokova, L. S., Medvedev, S. P., Zakian, S. M., Kabilov, M. R., Tupikin, А. Е., & Lavrik, O. I. (2023) · Доклады Российской академии наук Науки о жизни · doi:10.31857/s2686738922600959
Investigating the effects of ageing on DNA repair in mesenchymal stromal cells
Frommelt, T. (2024) · Queensland University of Technology · doi:10.5204/thesis.eprints.248588
Li, S., Fang, C., Yuan, Q., & Chen, X. (2026) · Translational Oncology · doi:10.1016/j.tranon.2026.102667
“It is vital for preserving genomic integrity and preventing mutational accumulation [19].”
- Authors
- Noren Hooten, N., Fitzpatrick, M., Kompaniez, K., Jacob, K. D., Moore, B. R., Nagle, J., Barnes, J., Lohani, A., & Evans, M. K.
- Affiliations
- Laboratory of Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224
- National Institutes of Health (US)
- Corresponding author
- Evans, Michele K.
- ORCID
- Evans, Michele K.
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2012-10-26
- Volume
- 4
- Issue
- 10
- Pages
- 674-685
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC3517938
- OpenAlex
- W2185198196
- Cited by
- 44
- References
- 52
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (52006134)
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- NEIL1, PARP1, base excision repair, oxidative DNA damage, poly(ADP-ribosyl)ation, DNA glycosylase, OGG1, BRCT domain, protein-protein interaction
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Aging, Animals, DNA Repair, Glutathione Transferase, HeLa Cells, Humans, Mice, Inbred C57BL, Poly(ADP-ribose) Polymerases, DNA Glycosylases, Mice
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